The long term objective of this project is to determine the neural mechanisms of opioid inhibition of nociception at the spinal cord level and compare this effect with the opioid inhibition of nociception at the brainstem level. The ultimate goal is a better understanding of the mechanisms of the opioid blockade of pain with the hope that this understanding will lead to the rational development of analgesic drugs and other treatments which are more selective, less addicting and lead to fewer side effects. The development of epidural analgesics is an example of the treatments which a more thorough understanding of the opioid mechanisms has led to. The specific aims of the next grant period are to: l) determine the effects of activating and inactivating specific opioid receptor subtypes on the responses of extra- and intracellularly recorded lamina I and II neurons. 2) determine the site of action of different opioid receptor subtypes in lamina I and II (pre- vs. postsynaptic). 3) determine the relationship of activating specific opioid receptor subtypes on nociceptive behavior in the rat and correlate these effects with the production of FOS onco-protein at both the spinal and brainstem level. 4) determine at which site, spinal cord or brainstem, specific opioid agonists are most effective when applied systemically. A series of in vivo extra and intracellular recording studies is proposed in anesthetized cats combined with microiontophoresis and intrathecal and systemic application of opioids to address the first specific aim. In vitro whole cell patch clamping experiments in spinal cord slices are proposed to address specific aim 2. Whole animal behavioral studies in rats combined with immunocytochemistry of FOS protein are proposed to address specific aims 3 and 4.